There is a high need for new agents that are effective and safe for treating betaherpesvirus and gammaherpesvirus related emerging infections. A new series of purine nucleoside analogs, the methylenecyclopropanes (MP), have been shown to be promising antiviral agents with a very unusual spectrum of activity which includes the beta- and gammaherpeviruses, which has not been seen with existing anti-herpes agents. The first generation of MP compounds were biosteric analogs of acyclovir with the C-O-C moiety replaced by the methylenecyclopropane moiety. A second generation of MP analogues, the 2,2-bis-hydroxymethyl series, exhibited very good activity against HCMV. In both cases, the Z- and E-isomers were generated, with the Z isomers demonstrating the best overall potency. A limited number of analogues of both the first and second generation of MP's have exhibited some of the most potent inhibition of HHV-6 and HHV-8 replication so far identified. The hypothesis of this proposal is that extensive chemical modification of the MP compounds will identify new molecules with even greater potency and efficacy specifically against HHV-6 and HHV-8. Proven medicinal chemistry structure activity relationship (SAR) approaches will be used to improve the potency of the MP compound series against HHV-6 and HHV-8. The overall goal of this proposal is to develop novel therapies for the emerging infectious diseases HHV-6 and HHV-8. The specific objective of this proposal is to chemically optimize the MP series of compounds to improve the potency against HHV-6 and HHV-8. Lead MP compounds should also maintain activity against HCMV and would also be useful for treating these infections as well. There is no good antiviral drug with this unique profile. The major milestone of this proposal is to identify lead compounds (3-5) with excellent HHV-6 and HHV-8 inhibitory activity (<1?m) with minimum cytotoxicity in primary HEL299 cells (>100?m). Data generated in these studies will further justify their future evaluation in animal studies (SBIR Phase II), which will be used to identify a clinical candidate and support a subsequent application for Phase I/II HHV-6/-8 human clinical studies. This proposal has the following specific aims and milestones: PUBLIC HEALTH RELEVANCE: The hypothesis of this proposal is that extensive chemical modification of the MP compounds will identify new molecules with even greater potency and efficacy specifically against HHV-6 and HHV-8. Proven medicinal chemistry structure activity relationship (SAR) approaches will be used to improve the potency of the MP compound series against HHV-6 and HHV-8. The overall goal of this proposal is to develop novel therapies for the emerging infectious diseases HHV-6 and HHV-8.